Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that is widely distributed in the central and peripheral nervous systems. NPY is a member of the pancreatic polypeptide family that also includes peptide YY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev. Toxicol., 32, 309, 1993). NPY elicits its physiological effects by activation of at least six receptor subtypes designated Y1, Y2, Y3, Y4, Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998; Michel, M. et al., Pharmacol. Rev., 50, 143, 1998). Central administration of NPY to animals causes dramatically increased food intake and decreased energy expenditure (Stanley, B. and Leibowitz, S., Proc. Natl. Acad. Sci. USA 82: 3940, 1985; Billington et al., Am J. Physiol., 260, R321, 1991). These effects are believed to be mediated at least in part by activation of the NPY Y1 receptor subtype.
In addition to the treatment of metabolic and eating disorders, NPY Y1 receptor antagonists have potential therapeutic utility in the areas of pain, sexual dysfunction, congestive heart failure, cerebral hemorrhage, anxiety, depression, epileptic seizures, sleep disorders, migraine and allergic rhinitis. Thus, NPY Y1 and its regulatory pathways make compelling targets for a wide range of therapies and particularly in the development of obesity therapies.
Substituted phenyl compounds having activity against formation of nitrogen monoxide (NO) have been reported in Japanese Kokai Patent Application No. Hei 10[1998]-101658. Disclosed are compounds having the formula:
where the various elements are defined therein. An illustrative compound of that series is:
